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Extensive literature search on grayanotoxins and 5hydroxymethylfurfural
Bredsdorff, Lea; Olesen, Pelle Thonning; Sharma, Anoop Kumar; Hansen, Max; Jørgensen, Kevin; Ekstrøm, Jeannette; RavnHaren, Gitte; Skjolding, Lars Michael; Baun, Anders; Beltoft, Vibe Meister
Published in: EFSA Supporting Publications
Link to article, DOI: 10.2903/sp.efsa.2020.EN-1920
Publication date: 2020
Document Version Publisher's PDF, also known as Version of record
Link back to DTU Orbit
Citation (APA): Bredsdorff, L., Olesen, P. T., Sharma, A. K., Hansen, M., Jørgensen, K., Ekstrøm, J., RavnHaren, G., Skjolding, L. M., Baun, A., & Beltoft, V. M. (2020). Extensive literature search on grayanotoxins and 5 hydroxymethylfurfural. EFSA Supporting Publications, 17(8), [1920E]. https://doi.org/10.2903/sp.efsa.2020.EN- 1920
Extensive literature search on grayanotoxins and 5-hydroxymethylfurfural
Lea Bredsdorff, Pelle Thonning Olesen, Anoop Kumar Sharma, Max Hansen, Kevin Jørgensen, Jeannette Ekstrøm, Gitte Ravn-Haren, Lars Michael Skjolding, Anders Baun and
Vibe Meister Beltoft
Abstract
An extensive literature search to identify and collect studies related to the toxicity of grayanotoxins
and 5-hydroxymethylfurfural (5-HMF) was performed in the three databases PubMed, Web of Science
and SciFinder® for six and four Areas, respectively. After combination of the searches from the three databases and removal of the duplicates, the total number of references for the grayanotoxins was
652 and for 5-HMF Area 1b was 3,862, for Area 2b was 37, for Area 3b was 221 and for Area 4b was 500. The evaluation of all retrieved references for relevance by screening the title and abstract (if
available) and applying eligibility criteria (inclusion/exclusion) resulted in a total number of relevant
references for the grayanotoxins for Area 1a of 71, for Area 2a of 3, for Area 3a of 5, for Area 4a of 75, for Area 5a of 141, and for Area 6a of 78 and for 5-HMF for Area 1b of 55, for Area 2b of 14, for
Area 3b of 15 and for Area 4b of 8.
© European Food Safety Authority, 2020
Key words: grayanotoxin, andromedotoxin, 5-hydroxymethylfurfural, 5-HMF, toxicity, bee health, extensive literature search
Question number: EFSA-Q-2020-00540
www.efsa.europa.eu/publications 2 EFSA Supporting publication 2020:EN-1920
Disclaimer: The present document has been produced and adopted by the bodies identified above
as author(s). This task has been carried out exclusively by the author(s) in the context of a contract
between the European Food Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the
Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the
conclusions reached in the present document, without prejudice to the rights of the authors.
Suggested citation: National Food Institute, Technical University of Denmark, Bredsdorff L, Olesen PL, Sharma AK, Hansen M, Jørgensen K, Ekstrøm J, Ravn-Haren G, Skjolding LM, Baun A and Beltoft VM, 2020. Extensive literature search on grayanotoxins and 5-hydroxymethylfurfural. EFSA
supporting publication 2020:EN-1920. 52 pp. doi:10.2903/sp.efsa.2020.EN-1920
ISSN: 2397-8325
Reproduction is authorised provided the source is acknowledged.
The present document has been produced and adopted by the bodies identified above as author. This task has been carried out exclusively by the author in the context of a contract between the European Food Safety Authority and the author, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the author.
Summary
The overall aim of this assignment was to identify and collect all relevant literature related to the toxicity of grayanotoxins and 5-hydroxymethylfurfural (5-HMF) to support the preparatory work for
the hazard identification and characterisation steps in the human health risk assessment of these substances.
Initially, one tailored search string for grayanotoxins and four tailored search strings for 5-HMF were designed in collaboration with EFSA to retrieve all potentially relevant studies within the following
Areas:
Grayanotoxins:
Area 2a: Data on occurrence in food.
Area 3a: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in
experimental animals and humans and from in vitro studies.
Area 4a: Data on toxicity in experimental animals.
Area 5a: Data on in vitro and in vivo genotoxicity, in vitro studies and mode of action.
Area 6a: Data on observations in humans (including epidemiological studies, case reports,
biomarkers of exposure).
Area 2b: Data on occurrence in bee feed and honey.
Area 3b: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in bees and
from in vitro studies.
Area 4b: Data on toxicity in bees.
The search strings were tailored to the databases PubMed, Web of Science and SciFinder® and consisted of one major step for the grayanotoxins and two major steps for 5-HMF, each designed to
suit the respective databases.
Combinations of search terms were used, starting with broad searches for the two substance groups, including synonyms and abbreviations (step 1) and was for 5-HMF followed by an Area specific step
with the addition of search terms relevant to each Area (step 2).
Then tailored search strings were employed to retrieve all relevant studies from the three databases.
All retrieved references were exported as separate files into EndNoteTM (version X9). Duplicate studies
were then removed after combining the three EndNoteTM files, into one file for the grayanotoxins and into one single combined file per Area for 5-HMF. The EndNote libraries are available on the
Knowledge Junction community of EFSA on Zenodo, at: http://doi.org/10.5281/zenodo.3972112
The combined number of references from each database was 652 for the grayanotoxins, and was
3,862 from Area 1b, 37 from Area 2b, 221 from Area 3b and 500 from Area 4b for 5-HMF.
All retrieved references were then evaluated for relevance by applying eligibility criteria
(inclusion/exclusion). The selection for relevance was conducted by screening the title and abstract (if available) and all the retrieved studies were ultimately sorted into one of the following two categories:
Relevant to the research objectives: References ultimately evaluated to be relevant were
included in this category.
Not relevant to the research objectives: References ultimately evaluated not to be in-scope
were included in this category.
The results of the reference selection process were reported in summary tables (Excel files), one for
each Area, and for the grayanotoxins an additional table containing all references for the primary sorting. The summary tables are available on the Knowledge Junction community of EFSA
on Zenodo, at: http://doi.org/10.5281/zenodo.3972112. The summary tables include all pertinent information for each of the references in the ‘Relevant’ category as identified by the
eligibility criteria suggested by the Contractor and agreed by EFSA which could be retrieved from the
title and abstract (when available). The summary tables also include references in the ‘Not relevant’ categories, but without any study details except for including the reason for exclusion for the ‘Not
relevant’ references, i.e. not target compound or not relevant for the specific Area is presented.
The evaluation for relevance resulted in a total number of relevant references for grayanotoxins for
Area 1a of 71, for Area 2a of 3, for Area 3a of 5 for Area 4a of 75, for Area 5a of 141, and for Area 6a of 78 and for 5-HMF for Area 1b of 55, for Area 2b of 14, for Area 3b of 15, and for Area 4b of 8.
Table of contents
Abstract ......................................................................................................................................... 1 Summary ....................................................................................................................................... 3 1. Introduction ........................................................................................................................ 6 1.1. Background and Terms of Reference as provided by EFSA ..................................................... 6 1.1.1. Background as provided by EFSA ......................................................................................... 6 1.1.2. Objectives as provided by EFSA ........................................................................................... 7 2. Methodologies .................................................................................................................... 8 2.1. Objective 1 ......................................................................................................................... 8 2.1.1. Task 1 Developing tailored search strategies and search strings for collecting relevant studies 8 2.2. Objective 2 ......................................................................................................................... 9 2.2.1. Task 2 Execution of the extensive literature searches using the tailored search strings
developed in task 1 ............................................................................................................. 9 2.3. Objective 3 ......................................................................................................................... 9 2.3.1. Task 3 Selection of all relevant studies retrieved by the extensive literature searches .............. 9 3. Results ............................................................................................................................. 10 3.1. Objective 1 ....................................................................................................................... 10 3.1.1. Task 1 Developing tailored search strategies and search strings for collecting relevant studies10 3.2. Objective 2 ....................................................................................................................... 14 3.2.1. Task 2 Execution of four extensive literature searches using the tailored search strings
developed in task 1 ........................................................................................................... 14 3.3. Objective 3 ....................................................................................................................... 15 3.3.1. Task 3 Selection of all relevant studies retrieved by the extensive literature searches ............ 15 4. Conclusions ...................................................................................................................... 16 References ................................................................................................................................... 17 Abbreviations ............................................................................................................................... 18
Log file for the tailored search strings to retrieve all relevant data pertinent to the risk assessment and characterisation of grayanotoxins ........................................................ 19
Log file for the tailored search strings to retrieve all relevant data pertinent to the
risk assessment and characterisation of 5-HMF.................................................................... 20 Reference lists .................................................................................................... 23
1. Introduction
1.1. Background and Terms of Reference as provided by EFSA
This contract was awarded by EFSA to:
Contractor: National Food Institute, Technical University of Denmark
Contract title: Extensive literature search on grayanotoxins and 5-Hydroxymethylfurfural
Contract number: NP/EFSA/BIOCONTAM/2019/03
1.1.1. Background as provided by EFSA
The Unit on Biological Hazards and Contaminants (BIOCONTAM Unit) supports the Panel on
Contaminants in the Food Chain (CONTAM Panel), which provides scientific advice on contaminants in the food chain and undesirable substances such as natural toxicants, mycotoxins and residues of
unauthorised substances.
EFSA expects to receive soon two new mandates from the European Commission for scientific
opinions. One, on the health risks related to the presence grayanotoxins in honey and another one on the risks of 5-Hydroxymethylfurfural for bee health. These mandates will be allocated to the CONTAM
Panel and Working Groups will be established to develop these opinions.
To support the preparatory work for these opinions, EFSA wishes to outsource an Extensive Literature Search (ELS) as well as the selection of relevant studies by screening of title and abstract related to
a) the chemical identity and characterisation, occurrence in food, toxicokinetics and toxicity of
grayanotoxins
b) the chemical identity, characterisation, formation and occurrence in bee feed and honey,
toxicokinetics and toxicity in bees or related species of 5-Hydroxymethylfurfural.
Grayanotoxins, also known as andromedotoxin, acetylandromedol or rhodotoxin are diterpens present
in plants belonging to the Ericaceae family. Grayanotoxins can also be present in products originating from such plants in particular in honey. Uptake of grayanotoxins has been associated with a series of
adverse effects on the nervous system in humans1. The EFSA compendium on botanicals mentions
grayanotoxins as chemicals of concern in leaves and flowers of Rhododendron species2.
5-Hydroxymethylfurfural (HMF) is a product of the Maillard reaction i.e. is formed during the thermal treatment of carbohydrate containing foods. It can be found in a variety of foods like fruit juices, jam,
chocolates, cereal bars but also in honey. HMF has been shown to exert toxicity in animal experiments and to have potentially adverse effects in humans3. It is also toxic to bees and
application of HMF-containing bee feed has been associated with shorter life span and increased
mortality in bees4,5,6.
1 Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA, 2012. Grayanotoxin poisoning:
'mad honey disease' and beyond. Cardiovasc Toxicol. Sep;12 (3): 208-15. doi: 10.1007/s12012-012-9162-2. 2 European Food Safety Authority; Compendium of botanicals that have been reported to contain toxic, addictive, psychotropic
or other substances of concern on request of EFSA. EFSA Journal 2009; 7(9):281. [100 pp.]. doi:10.2903/j.efsa.2009.281. Available online: www.efsa.europa.eu.
3 Abraham K, Gürtler R, Berg K, Heinemeyer G, Lampen A, Appel KE, 2011.Toxicology and risk assessment of 5-
Hydroxymethylfurfural in food. Mol Nutr Food Res. 2011 May;55(5):667-78. doi: 10.1002/mnfr.201000564. Epub 2011 Apr 4. 4 LeBlanc BW, Eggleston G, Sammataro D, Cornett C, Dufault R, Deeby T, St Cyr E, 2009. Formation of hydroxymethylfurfural
in domestic high-fructose corn syrup and its toxicity to the honey bee (Apis mellifera). J Agric Food Chem. 2009 Aug 26;57(16):7369-76. doi: 10.1021/jf9014526.
The contractor should ensure that all the steps for conducting the ELS are properly documented and
reported.
This call is based on EFSA’s 2019 draft Work Programme for grants and operational procurements as
presented in Annex IX of the draft Programming Document 2019 – 2021, available on the EFSA’s website7.
1.1.2. Objectives as provided by EFSA
The objectives of the contract are as follows:
Objective 1 a): To develop tailored search strategies to retrieve studies (including reviews and grey
literature) pertinent to the risk assessment and characterisation of grayanotoxins (applying no time limit).
Area 1a: Data on chemical identification, characterisation and formation
Area 2a: Data on occurrence in food
Area 3a: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in
experimental animals and humans and from in vitro studies. Area 4a: Data on toxicity in experimental animals and in vitro
Area 5a: Data on in vitro and in vivo genotoxicity and mode of action
Area 6a: Data on observations in humans (including epidemiological studies, case reports,
biomarkers of exposure)
Objective 1 b): To develop tailored search strategies to retrieve studies (including reviews and grey
literature) pertinent to the risk assessment and characterisation of 5-Hydroxymethylfurfural in bees
Area 1b: Data on chemical identification, characterisation and formation
Area 2b: Data on occurrence in bee feed and honey
Area 3b: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in bees and
from in vitro studies. Area 4b: Data on toxicity in bees
The search strategies proposed by the contractor will be discussed and agreed with EFSA before proceeding with the actual searches.
• Objective 2: To carry out the extensive literature search (ELS) using the tailored search
strings developed by the contractor and agreed by EFSA for identifying studies.
• Objective 3: To screen the titles and abstracts for relevance to the risk assessment. To prepare a file compatible with EndNoteTM (RIS file) with the relevant literature and a table
summarising the relevant studies. These should contain the studies considered as relevant
applying the eligibility criteria (for inclusion/exclusion of studies) that have to be developed by the contractor. The file compatible with EndNoteTM (RIS file) and table should be
organised by group of compounds and by area.
5 Zirbes L, Nguyen BK, de Graaf DC, De Meulenaer B, Reybroeck W, Haubruge E, Saegerman C, 2013. Hydroxymethylfurfural:
a possible emergent cause of honey bee mortality? J Agric Food Chem. 2013 Dec 11;61(49):11865-70. doi: 10.1021/jf403280n. Epub 2013 Dec 3.
6 Shapla UM, Solayman M, Alam N, Khalil MI, Gan SH, 2018. 5-Hydroxymethylfurfural (HMF) levels in honey and other food
products: effects on bees and human health. Chem Cent J. 2018 Apr 4;12(1):35. doi: 10.1186/s13065-018-0408-3. 7 http://www.efsa.europa.eu/sites/default/files/corporate_publications/files/amp1921.pdf
2. Methodologies
The methodology for systematic reviews including guidance for development and optimisation of a search strategy and for selecting relevant studies has been described by EFSA (2010). This
methodology was implemented as appropriate in the Tasks described below.
2.1. Objective 1
2.1.1. Task 1 Developing tailored search strategies and search strings for
collecting relevant studies
Tailored search strings were developed for identifying all potentially relevant studies pertinent to the
risk assessment and characterisation of grayanotoxins and to the risk assessment and characterisation of 5-HMF in bees.
The search strings were tailored to the databases PubMed, Web of Science and SciFinder®. The search consisted of one (grayanotoxins) or two (5-HMF) major steps designed to suit the respective
databases. In PubMed, searches were made with the All fields [ALL] tag. In Web of Science, searches were made in Topic including title, abstract, author keywords and keywords plus® and in ‘All
Databases’ for the most comprehensive result. In SciFinder® CAS registry numbers were used instead
of substance names as substances are indexed with links to CAS Registry, which makes search strings with CAS registry numbers preferable. Boolean operators were used for combinations of search terms.
In SciFinder® patents were excluded from the search.
The first major step consisted of separate broad searches for grayanotoxins and 5-HMF including
synonyms, derivatives and CAS Registry Numbers to retrieve the largest number of potentially
relevant studies on grayanotoxins within Area 1a-6a and 5-HMF within Area 1b-4b. The search strings were presented and discussed with EFSA at the kick-off meeting.
2.1.1.1. Grayanotoxins
Due to the expected relatively low number of references identified in the literature search with the use
of the major search string, no further limitations were applied to the search string. This means that Area-specific search strings were not applied. Instead, the selection of relevant studies was performed
in two steps. The first step was a primary sorting of all references into relevant or potentially relevant
for Area 1a to 6a or not relevant for any Areas. The references not considered relevant for any Areas were not considered further. This primary sorting was performed independently by two team
members. The results were then compared to make sure that all relevant and potentially relevant references had been identified. In cases of doubt, references were included for final assessment of
relevance by the Area-specific expert in the second step of the selection of relevant studies as
described under Objective 3 (Section 3.3.).
At the kick-off meeting, it was agreed with EFSA that all relevant in vitro studies would be included in
Area 5a, which will then include in vitro studies with toxicological endpoints in addition to in vitro and in vivo genotoxicity studies and mode of action (MoA) studies. The type of study (toxicity, genotoxicity
and MoA) will clearly be stated for each reference in the summary table for Area 5a. Area 4a will then
only include in vivo toxicity in experimental animals. It was also agreed to include studies in pets such as cats and dogs, but to exclude studies in livestock as relevant experimental animals in Area 4a and
to include in silico studies in Area 5a.
2.1.1.2. 5-HMF
A second step was applied to the literature search for 5-HMF. This step was Area-specific with the addition of search terms relevant to each specific Area.
Search terms were identified in collaboration with relevant members of the project team to identify as
many relevant as possible. The search strings were developed in order to retrieve the largest number
of potentially relevant studies on 5-HMF within Area 1b-4b. The search strings were presented and discussed with EFSA at the kick-off meeting.
2.2. Objective 2
2.2.1. Task 2 Execution of the extensive literature searches using the
tailored search strings developed in task 1
The tailored search strings developed in Task 1 and agreed upon by EFSA were employed to retrieve all relevant studies from the databases PubMed, Web of Science and SciFinder® on grayanotoxins and
5-HMF.
No limitation to publication year was applied. Language was limited to English only.
All references identified in the extensive literature searches (ELS) in PubMed, Web of Science and
SciFinder® were exported as separate files into EndNoteTM. Title, author, journal, year of publication and abstract were included for each study imported to EndNoteTM and the number of references
resulting from each of the three databases was recorded in a log file (example in Table 1). Duplicate studies were removed after combining the three EndNoteTM files into one single combined file for each
substance group.
Table 1: OBJECTIVE: Develop tailored search strategies to retrieve all relevant data grayanotoxins
Date of
exported to EndNoteTM
2.3. Objective 3
2.3.1. Task 3 Selection of all relevant studies retrieved by the extensive
literature searches
All studies retrieved by the ELS and imported into the combined EndNoteTM files (Task 2) were evaluated for relevance by applying eligibility criteria (inclusion/exclusion) for each subject Area (1a-
6a and 1b-4b) developed by the Contractor and agreed upon by EFSA.
The selection for relevance was conducted by screening their title and abstract (if available) and all the retrieved studies were ultimately sorted into one of the following two categories:
Relevant to the research objectives: References ultimately evaluated to be relevant were
included in this category. The reviewer consulted the full paper if possible in cases where relevance was uncertain. If relevance remained uncertain, the references were included in this
category, as a conservative approach.
Not relevant to the research objectives: References ultimately evaluated not to be in-scope
were included in this category.
To ensure a uniform understanding of the eligibility criteria in each Area, these were discussed in an internal meeting before all references were assessed for relevance.
Each study was individually assessed by two reviewers in order to prevent the introduction of errors
and personal bias. In the possible event of disagreements between reviewers a third member of the project team assisted in solving the specific issue as recommended by EFSA (2010).
The results of the reference selection process were reported in summary tables, one table per Area (1a-6a and 1b-4b), and an additional table with the primary sorting for the grayanotoxins. The
summary tables include all pertinent information from each of the relevant studies as identified by the
eligibility criteria developed by the Contractor and agreed with EFSA. Additional fields for potential relevance for other Areas, the person(s) responsible for the screening and comments were also
included in the summary tables.
All references found relevant for the hazard identification and characterisation of grayanotoxins and
the risk assessment and characterisation of 5-HMF in bees within Area 1a-6a and 1b-4b were collected in EndNoteTM files (in one single EndNoteTM file for grayanotoxins and in one EndNoteTM file per Area
for 5-HMF) including all indexed fields per reference (i.e. title, author, publication year, journal and
abstract).
All relevant studies were collected in a reference list, one list per Area per substance group, see
Appendix C.
3. Results
3.1. Objective 1
3.1.1. Task 1 Developing tailored search strategies and search strings for
collecting relevant studies
The tailored search strings were developed in order to retrieve the largest number of potentially relevant studies related to the chemical identity and characterisation, occurrence in food,
toxicokinetics and toxicity of grayanotoxins within Area 1a-6a and the chemical identity, characterisation, formation and occurrence in bee feed and honey, toxicokinetics and toxicity in bees
or related species of 5-HMF within Area 1b-4b.
The suggested search strings for grayanotoxins and 5-HMF are presented below and were submitted to EFSA on 24 April 2020 (email) as part of Deliverable 1.
The search string for step 1 was developed in order to capture all known and potentially unknown grayanotoxins and their derivatives, and 5-HMF and its deviates.
The search string for step 2, Area 1a, was developed based on the experiences obtained in a similar
procurement carried out for EFSA i.e. ‘Extensive literature search for studies related to fumonisins and their modified forms’, final report approved by EFSA on 2 December 2016. In this procurement, the
search terms were combined and tested in the databases PubMed and Web of Science to develop the most sensitive and appropriate search string.
The search strings for step 2, Area 3b and 4b were developed by using search terms identified from
OECD Test Guideline 213 (OECD 1998) and 245 (OECD 2017) and US EPA Honey Bee Acute Contact Toxicity Test (US EPA 2012).
The search strings were tested by assessing whether they retrieved relevant papers already known to the project team as recommended in EFSA (2010).
Boolean operators were used in the proposed search strings. “OR” expands the amount of references returned when used in a search string as just one of the search terms need to be present in the
returned references. “AND” narrows the amount of references returned as all of the search terms
need to be present in the returned references. The Boolean operator “NOT” excludes references
containing specific search terms and is to be used with caution. “*” symbolises truncation and is used for finding singular and plural forms of words and various endings. Both PubMed and Web of Science
use an asterisk as their truncation symbol.
3.1.1.1. Objective 1a Grayanotoxins
Step 1:
The search string agreed for step 1 in PubMed and Web of Science is as follows:
Grayano* OR
OR
Asebotoxin*
The search term grayanane* is included to catch potential relevant references that may include
grayanotoxins in grayanane diterpenoids.
The search string agreed for step 1 in SciFinder® includes 18 isomers of grayanotoxin (grayanotoxin I- XV and XVII-XIX) and is as follows:
4720-09-6
OR
4678-44-8
OR
4678-45-9
OR
30272-17-4
OR
30272-18-5
OR
30460-36-7
OR
30460-59-4
OR
30460-60-7
OR
30460-58-3
OR
36660-75-0
OR
33880-98-7
OR
35928-08-6
OR
35928-07-5
OR
39012-12-9
OR
39012-13-0
OR
59740-27-1
OR
70474-76-9
OR
75829-08-2
Step 1:
The search string agreed for step 1 in PubMed and Web of Science is as follows:
5-hydroxymethylfurfural
OR HMF
OR 5-HMF
OR 5-hydroxymethyl-2-furfuraldehyde
OR 5-(hydroxymethyl)furan-2-carbaldehyde
The search string agreed for step 1 in SciFinder® is as follows:
67-47-0
For PubMed:
AND (chem* OR analy* OR identi* OR charact* OR detect* OR determin* OR method* OR form* OR
degrad* OR hydroly* OR reaction* OR GC* OR HPLC OR LC-MS OR ICP-MS)
AND
(honey OR syrup OR fructose OR HFCS OR sugar OR bee feed OR bee OR stingless bee OR honey bee
OR honey-bee OR bumblebee OR solitary bee OR apis OR pollinator)
For Web of Science:
AND
For SciFinder®:
AND
NOT
(waste oil OR one-pot OR zirconium OR ruthenium OR silver OR fuel OR biofuel OR bamboo OR
eutectic OR ferment OR humins).
Area 2b: Data on occurrence in bee feed and honey
AND (honey OR syrup OR fructose OR HFCS OR sugar)
AND
vitro studies.
AND (bee* OR stingless bee* OR honey bee* OR honeybee* OR honey-bee* OR bumblebee* OR
solitary bee* OR apis OR pollinator)
AND
(toxicokinetic* OR absorp* OR distribution OR metaboli* OR excret* OR vitro)
Area 4b: Data on toxicity in bees
AND (bee* OR stingless bee* OR honey bee* OR honeybee* OR honey-bee* OR bumblebee* OR
solitary bee* OR apis OR pollinator)
AND
(toxic* OR survi* OR morta* OR hatch* OR lethal* OR chronic* OR repro* OR offspring OR brood OR
colony collapse disorder OR CCD OR diet* OR consump* OR behaviour OR feed* OR abnormalities*
OR cramp* OR moribund OR apathy OR vomit* OR lethargy OR ataxia OR OECD 213 OR OECD 245
OR OPPTS 850.3020)
3.2. Objective 2
3.2.1. Task 2 Execution of four extensive literature searches using the
tailored search strings developed in task 1
The number of references resulting from each of the tailored search strings in each of the three databases PubMed, Web of Science and SciFinder® were recorded in log files for grayanotoxins and 5-
HMF, see Appendix A and B.
The number of references from each database, as well as the total number of references after removal of the duplicates (combined) are summarised in Table 2 (grayanotoxins) and Table 3 (5-
HMF). For the grayanotoxins the number of references found relevant in the primary sorting for each Area is presented in Table 4. The duplicates in the combined files for the primary sorting for the
grayanotoxins and for each Area 1b-4b for 5-HMF were removed by the EndNoteTM tool. The EndNoteTM tool is for various reasons not able to remove all duplicates, so remaining duplicates were
removed manually as part of Task 2 and during the execution of Task 3. The revised versions of the
combined EndNoteTM files were submitted as part of the final deliverable.
Table 2: Total number of references from PubMed, Web of Science and SciFinder® and the
combined number of references after removal of duplicates for grayanotoxins
Area PubMed Web of Science SciFinder® Combined total
All 256 628 260 652
Table 3: Total number of references from PubMed, Web of Science and SciFinder® and the combined number of references after removal of duplicates for 5-HMF
Area PubMed Web of Science SciFinder® Combined total
1b 901 2,127 2,298 3,862
2b 3 13 26 37
3b 7 198 29 221
4b 17 345 168 500
Table 4: Number of references found potentially relevant for each Area after the primary sorting for grayanotoxins
Area Number of references
3.3. Objective 3
3.3.1. Task 3 Selection of all relevant studies retrieved by the extensive
literature searches
The final protocol and project plan implemented by the Contractor to carry out the project was
submitted to EFSA on 10 July 2020 (by e-mail) as part of the draft final deliverable.
Grayanotoxins
The total number of relevant references for grayanotoxins Area 1a-6a is presented in Table 5.
Table 5: The total number of relevant references for grayanotoxins found for each Area
Area Number of relevant references
1a 71
2a 3
3a 5
4a 75
5a 141
6a 78
5-HMF
The total number of relevant references for 5-HMF Area 1b-4b is presented in Table 6.
Table 6: The total number of relevant references for 5-HMF found for each Area
Area Number of relevant references
1b 55
2b 14
3b 15
4b 8
Summary tables
A proposal for the information (eligibility criteria) to be included in the summary tables for each Area (1a-6a and 1b-4b) was submitted to EFSA on 24 April 2020, (e-mail) as part of Deliverable 1. The
proposed summary tables were discussed with EFSA at the kick-off meeting on 29 April 2020. EFSA
had a few suggestions for revisions, which were agreed at the kick-off meeting, and reflected in the minutes accepted by EFSA 6 May 2020 (e-mail).
Summary tables (Excel files) with at least 10 motivated excluded papers per group of substances and 10 motivated included papers per group of substances were submitted to EFSA on 18 May 2020,
(email) as part of Deliverable 2. These summary tables were discussed with EFSA at the interim
meeting on 25 May 2020. EFSA had a few suggestions for revisions, which were agreed at the interim meeting and reflected in the minutes accepted by EFSA May 27 2020 (MS-TEAMS). At the interim
meeting EFSA supplied DTU with a Technical Report from EFSA on honey from rhododendron for use in plant protection as rodenticide (EFSA, 2016). This report was not identified in the ELS, but is
included in the reference list (Section 6).
Summary tables (Excel files) were prepared, one table for each Area 1a-6a (grayanotoxins) and 1b-4b
(5-HMF). The summary tables include all pertinent information for each of the references in the
‘Relevant’ category as identified by the eligibility criteria suggested by the Contractor and agreed by EFSA, which could be retrieved from the title and abstract (when available). For the grayanotoxins an
additional summary table for the primary sorting, containing all references was included. The Area- specific summary tables also include ‘Not relevant’ studies, but without any study details. For the ‘Not
relevant’ studies, the reason for exclusion, i.e. not target compound or not relevant for the specific
Area, is presented. In addition, there is also an indication if a specific reference is considered of potential relevance for other Area(s).
All references included in the ‘Relevant’ category appear on a green background and all references included in the ‘Not relevant’ category appear on a white background. References that were identified
in one Area to be of potential relevance for another Area were evaluated by the teammember
responsible for that specific Area. In most cases, this did not result in any additional references for any of the Areas.
Several measures were enforced to limit the amount of not-relevant references in 5-HMF, Area 1b, and are reflected in the search strings in Section 3.1.1 and in Appendix B. In addition, it was agreed
with EFSA that analytic methods not including analysis of 5-HMF in bee feed or honey were considered not relevant.
For 5-HMF, Area 3b and 4b, it was agreed to include studies with other types of pollinators relevant
for bee health, due to the limited amount of data on toxicokinetics and toxicity of 5-HMF in bees.
A total of 11 summary tables were submitted to EFSA on 10 July 2020, as part of the draft final
deliverable.
3.3.1.1. EndNoteTM files
In the EndNoteTM files (one file for the grayanotoxins and one file per Area for 5-HMF) all references
were separated in two folders:
1. Relevant – green: Containing references evaluated to be of relevance for this procurement.
2. Not relevant: Containing references evaluated not to be in-scope for this procurement.
A total of 20 EndNoteTM files were submitted to EFSA on 10 July 2020, (by e-mail) as part of the draft final deliverable.
3.3.1.2. Reference lists
All relevant references from each Area 1a-6a (grayanotoxins) and Area 1b-4b (5-HMF) were collected
in a reference list (Word file). The reference lists are included in Appendix C to this report.
4. Conclusions
An ELS to identify and collect all studies related to the toxicity of grayanotoxins and 5-HMF was
performed in the three databases PubMed, Web of Science and SciFinder® for six and four Areas, respectively.
The combined number of references from each database was 652 for the grayanotoxins and 3862 from Area 1b, 37 from Area 2b, 221 from Area 3b, and 500 from Area 4b for 5-HMF.
The evaluation of all retrieved references for relevance by screening of the title and abstract (if
available) and applying eligibility criteria (inclusion/exclusion) resulted in a total number of relevant references for grayanotoxins for Area 1a of 71, for Area 2a of 3, for Area 3a of 5 for Area 4a of 75, for
Area 5a of 141, and for Area 6a of 78 and for 5-HMF for Area 1b of 55, for Area 2b of 14, for Area 3b of 15, and for Area 4b of 8.
References
EFSA (European Food Safety Authority), 2010. Application of systematic review methodology to food and feed safety assessments to support decision making. EFSA Journal 2010;8(6):1637. 90 pp.
doi:10.2903/j.efsa.2010.1637
EFSA (European Food Safety Authority), 2017. Technical report on the outcome of the consultation
with Member States and EFSA on the basic substance application for honey from rhododendron for use in plant protection as rodenticide. EFSA supporting publication 2017:EN-1155. 54 pp.
OECD (1998), Test No. 213: Honeybees, Acute Oral Toxicity Test, OECD Guidelines for the Testing of
Chemicals, Section 2, OECD Publishing, Paris, https://doi.org/10.1787/9789264070165-en.
OECD (2017), Test No. 245: Honey Bee (Apis Mellifera L.), Chronic Oral Toxicity Test (10-Day
Feeding), OECD Guidelines for the Testing of Chemicals, Section 2, OECD Publishing, Paris, https://doi.org/10.1787/9789264284081-en.
US EPA (2012), Ecological Effects Test Guidelines OCSPP 850.3020: Honey Bee Acute Contact Toxicity
Test.
Abbreviations
5-HMF 5-hydroxymethylfurfural
ICP-MS Inductively coupled plasma mass spectrometry
LC-MS Liquid chromatography mass spectrometry
MoA Mode of action
CAS Chemical abstract service
ELS Extensive literature search
Log file for the tailored search strings to retrieve all relevant data pertinent to the risk assessment and characterisation of grayanotoxins
Database: PubMed
Search terms No of
asebotoxin* OR grayanane*
Search terms No of
asebotoxin* OR grayanane*
Date of search May 7, 2020
Search terms No of
actions
4720-09-6 OR 4678-44-8 OR 4678-45-9 OR 30272-17-4 OR 30272-18-5 OR 30460-36-7
OR 30460-59-4 OR 30460-60-7 OR 30460- 58-3 OR 36660-75-0 OR 33880-98-7 OR
35928-08-6 OR 35928-07-5 OR 39012-12-9
OR 39012-13-0 OR 59740-27-1 OR 70474- 76-9 OR 75829-08-2
260 Imported to EndNoteTM
Log file for the tailored search strings to retrieve all relevant data pertinent to the risk assessment and characterisation of 5-HMF
Database: PubMed (All fields)
Search #
Comments & follow- up actions
2312 #1
2 chem* OR analy* OR identi* OR charact* OR detect* OR determin* OR method* OR form* OR degrad* OR hydroly* OR reaction* OR GC OR HPLC OR LC-MS OR ICP-MS
17552028 #3
3 honey OR syrup OR fructose OR HFCS OR sugar OR bee OR stingless bee OR honey bee OR honeybee* OR honey-bee* OR bumblebee* OR solitary bee OR apis OR pollinator
554437 #6
5 #3 AND #4 901
#13 Area 1b imported
to EndNoteTM
6 honey OR syrup OR fructose OR HFCS OR sugar 532271
#7
8 #1 AND #6 947 #14
9 #7 AND #8 3 #15 Area 2b imported
to EndNoteTM
10 bee feed OR bee OR stingless bee OR honeybee* OR honey bee OR honey-bee* OR bumblebee* OR solitary bee OR apis OR pollinator
28691
#12
11 toxicokinetic* OR absorp* OR distribution OR metaboli* OR excret* OR vitro
7880649
#9
13 #11 AND #12 7 #17 Area 3b imported
to EndNoteTM
14 toxic* OR survi* OR morta* OR hatch* OR lethal* OR chronic* OR repro* OR offspring OR brood OR colony collapse disorder OR CCD OR diet* OR consump* OR behaviour OR feed* OR abnormalities* OR cramp* OR moribund OR apathy OR vomit* OR lethargy OR ataxia OR
OECD 213 OR OECD 245 OR OPPTS 850.3020
8689534
#10
to EndNoteTM
Database: WoS
Search #
6,169
2 chem* OR analy* OR identi* OR charact* OR detect* OR determin* OR method* OR form* OR degrad* OR hydroly* OR reaction* OR GC OR HPLC OR LC-MS OR ICP-MS
30,910,682
3 honey OR syrup OR fructose OR HFCS OR sugar OR bee feed OR bee OR stingless bee OR honey bee OR honey-bee OR bumblebee OR solitary bee OR apis OR pollinator
325,423
4 #1 AND #2 5,613
5 #4 AND #3 2,618
6 #5 and exclusion of categories ENERGY FUELS, MATERIALS SCIENCE and POLYMER SCIENCE
2,127 Area 1b imported to
EndNoteTM
6,324
8 honey OR syrup OR fructose OR HFCS OR sugar 293,215
9 Bee feed 2,647
10 #7 AND #8 AND #9 13 Area 2b imported to
EndNoteTM
11 (bee* OR stingless bee* OR honey bee* OR honeybee* OR honey-bee* OR bumblebee* OR solitary bee* OR apis OR pollinator)
8,661,437
12 (toxicokinetic* OR absorp* OR distribution OR metaboli* OR excret* OR vitro)
6,403,659
14 #13 AND #12 198 Area 3b imported to
EndNoteTM
15 (toxic* OR survi* OR morta* OR hatch* OR lethal* OR chronic* OR repro* OR offspring OR brood OR colony
collapse disorder OR CCD OR diet* OR consump* OR behaviour OR feed* OR abnormalities* OR cramp* OR moribund OR apathy OR vomit* OR lethargy OR ataxia OR OECD 213 OR OECD 245 OR OPPTS 850.3020)
10,617,779
EndNoteTM
Database: SciFinder®
preprints and reviews.
Search #
1 67-47-0 10424
2 #1 AND (chem OR analy OR identi OR charact OR detect OR determin OR method OR form OR degrad OR hydroly OR reaction OR GC OR HPLC OR LC-MS OR ICP-MS)
9577 The 9577 are based on excluding Medline due to a large number of hits (SciFinder search in Medline and CAPLUS)
3 #2 AND (bee OR stingless bee OR honey bee OR honeybee OR honey-bee OR bumblebee OR solitary bee OR apis OR pollinator)
168
4 #2 AND (honey OR syrup OR fructose OR HFCS OR sugar) 3657
5 #2 AND (bee feed) 28
6 #3 AND #4 AND #5 3672
7 #6 NOT (waste oil OR one-pot OR zirconium OR ruthenium OR silver OR fuel OR biofuel OR bamboo OR eutectic OR ferment OR humins)
2298 Area 1b imported to EndNoteTM
(only search in CAPLUS)
8 #1 AND (honey OR syrup OR fructose OR HFCS OR sugar) 3657
9 #1 AND (bee feed) 28
10 #8 AND #9 26 Area 2b imported to EndNoteTM
11 #1 AND (toxicokinetic OR absorp OR distribution OR metaboli OR excret OR vitro)
2110
12 #1 AND (bee OR stingless bee OR honey bee OR honeybee OR honey-bee OR bumblebee OR solitary bee OR apis OR pollinator)
172
14 #1 AND (toxic OR survi OR morta OR hatch OR lethal OR chronic OR repro OR offspring OR brood OR colony collapse disorder OR CCD OR diet OR consump OR behaviour OR feed OR abnormalities OR cramp OR moribund OR apathy
OR vomit OR lethargy OR ataxia OR OECD 213 OR OECD 245 OR OPPTS 850.3020)
2663
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Grayanotoxins Area 2a: Data on occurrence in food
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Grayanotoxins Area 3a: Data on toxicokinetics (absorption, distribution, metabolism, excretion) in experimental animals and humans and from in vitro studies
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Grayanotoxins Area 4a: Data on toxicity in experimental animals and in vitro
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